Recombinant granulocyte colony-stimulating factor administration to healthy volunteers: induction of immunophenotypically and functionally altered neutrophils via an effect on myeloid progenitor cells

Kerst, J. M.; Haas, Masja de; Schoot, C. Ellen van der; Slaper-Cortenbach, I. C. M.; Kleijer, Marion; Borne, A. E. G. K. Von Dem; Oers, R. H. J. Van

doi:10.1182/blood.v82.11.3265.3265

Cited by 156 publications

(57 citation statements)

References 44 publications

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“…The high affinity receptor for monomeric IgG, FcRI, is an early myeloid differentiation marker which is lost at the metamyelocyte stage during normal final maturation of PMN and is therefore not expressed on mature cells. It has been demonstrated that G-CSF acts on committed myeloid progenitor cells rather than on mature cells, so that the precursor cells are strongly induced by G-CSF to express FcRI, ultimately resulting in FcRI positive mature PMN (Kerst et al, 1993a). This study showed that by 96 h, FcRI expression was significantly increased with the 7 .…”

Section: Discussionmentioning

confidence: 67%

Ex vivo neutrophil function in response to three different doses of glycosylated rHuG‐CSF (Lenograstim)

Turzanski¹,

Crouch²,

Fletcher³

et al. 1997

Br J Haematol

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Summary. Granulocyte colony-stimulating factor (G-CSF) is being considered as adjuvant treatment for infections in non-neutropenic patients. Normal healthy donors were given rHuG-CSF (Lenograstim) at 2 . 5, 5 . 0 and 7 . 5 g/kg subcutaneously daily for 5 d. Polymorphonuclear leucocyte (PMN) function tests were carried out on peripheral blood PMN before the first injection and at 24 h and 96 h. Circulating PMN levels were also measured at these time intervals and found to be significantly increased with all doses by 24 and 96 h. Investigation of cell surface antigen expression revealed no changes in 2 integrin (CD11b/ CD18) expression. L-selectin (CD62L) expression was reduced with all doses by 96 h, this being significant with the 7 . 5 g/kg dose. FcRI (CD64) levels were significantly up-regulated with the 7 . 5 g/kg dose by 96 h whereas FcRIII (CD16) expression was found to be reduced during G-CSF treatment. Superoxide anion production was significantly increased in response to N-formylmethionylleucylphenylalanine (FMLP) and opsonized Staphylococcus epidermidis stimulation at 24 h and 96 h with the 5 . 0 and 7 . 5 g/kg doses. The initial rate of phagocytosis (0-2 min) appeared to have increased with the 7 . 5 and 5 . 0 g/kg doses at 96 and 24 h compared with PMN responses pretreatment, although these increases were not statistically significant. These results show that G-CSF enhances the functional responses of PMN stimulated by physiological agonists and may help in the treatment of infections.

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Section: Discussionmentioning

confidence: 67%

Ex vivo neutrophil function in response to three different doses of glycosylated rHuG‐CSF (Lenograstim)

Turzanski¹,

Crouch²,

Fletcher³

et al. 1997

Br J Haematol

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“…Finally, G-CSF administration was associated with a release into the circulation of LAP-positive immature granulocytes (characterized by low CD16 expression), thus suggesting that G-CSF in vivo can modulate the pathway of granulocytic maturation inducing surface expression of LAP in more immature granulocytes. Low levels of CD16 antigen expression in normal donors after exposure to G-CSF has several possible explanations, including release of immature neutrophils into the circulation, shedding of CD16 molecules as the consequence of induced cell activation and, upon in vitro culture, induction of apoptosis (Terstappen et al, 1990;Kerst et al, 1993;de Haas et al, 1994;Homburg et al, 1995). The release of immature neutrophils from the bone marrow is likely to play a more significant role in vivo for two reasons.…”

Section: Discussionmentioning

confidence: 99%

Leucocyte alkaline phosphatase identifies terminally differentiated normal neutrophils and its lack in chronic myelogenous leukaemia is not dependent on p210 tyrosine kinase activity

et al. 1999

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Summary. Leucocyte alkaline phosphatase (LAP) is a marker of post-mitotic granulocytes and its activity is reduced or absent in chronic myelogenous leukaemia (CML) granulocytes as a consequence of LAP messenger RNA (mRNA) deficiency. We provide evidence that along the granulocytic maturation in normal marrow, the acquisition of LAP surface expression, identified by the monoclonal antibody 1B12.1, was restricted to CD11b bright /CD16 bright positive cells. Moreover, in normal granulocytes, exposure to granulocyte colony-stimulating factor (G-CSF) in vitro and in vivo increased the cell surface expression of LAP. Although G-CSF was able to induce the LAP surface expression in CML granulocytes, the inhibition of p210 tyrosine kinase activity by genistein or CGP75148B failed to restore LAP mRNA expression and LAP protein synthesis. In conclusion, the acquisition of LAP protein on the cell surface of granulocytes follows CD16 antigen expression and can be considered as the last marker of terminally differentiated neutrophils. G-CSF is a potent regulator of the LAP mRNA expression and protein synthesis in normal and CML-derived neutrophils. The lack of direct activity of p210 tyrosine kinase on LAP mRNA expression in CML neutrophils supports the notion that the LAP defect in this disease could be related to a precocious and uncontrolled release of white blood cells from the bone marrow into the blood stream.

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“…One possibility is that G-CSF affects the functional activity of the granulocytes in the bone marrow, which are then released into the circulation with an increased functional capacity. Another investigation demonstrated that it was probably the neutrophils released from the bone marrow in response to G-CSF, which mediated the increase of CD64-dependent antibody-dependent cellular cytotoxicity (Kerst et al, 1993). Another possible explanation is that it is due to a shift to less mature forms of granulocytes, with activity different to normal mature cells.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo studies on the effect of G-CSF administration on the function of neutrophil granulocytes from healthy individuals have demonstrated enhanced adhesion to nylon wool, phagocytosis, luminol-enhanced chemiluminescence, degranulation, and expression of cell surface antigens (Rapoport et al, 1992;Kerst et al, 1993;de Haas et al, 1994;Xu et al, 1996;Höglund et al, 1997a). The levels of lactoferrin, HNL and elastase in serum/plasma increased during G-CSF administration and signs of mobilization of secretory vesicles had also been shown as further evidence for activation of neutrophil degranulation.…”

mentioning

confidence: 98%

“…Investigations of the effect on cell surface receptors have demonstrated increased expression of CD11b, CD18, CD35, CD32, CD64 and CD66b (Spiekermann et al, 1994). In particular, the induction of the high-affinity Fcg-receptor I (CD64) is remarkable, since it is not expressed on neutrophils from normal healthy individuals (Kerst et al, 1993;Valerius et al, 1993). On the other hand, the chemokinetic and chemotactic responses of neutrophils were reduced by G-CSF administration and lucigenin-enhanced chemiluminescence was unchanged, indicating that the oxidative metabolism was uneffected.…”

mentioning

confidence: 99%

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Effects of in vivo administration of G‐CSF on neutrophil and eosinophil adhesion

et al. 1997

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The effect in vivo of G‐CSF on neutrophil and eosinophil adhesion was studied after subcutaneous administration to six healthy individuals of human recombinant glycosylated G‐CSF (lenograstim) (3 μg/kg) for 6 consecutive days. Basal adhesion and adhesion to E‐selectin, VCAM‐1 and ICAM‐1 of neutrophil and eosinophil granulocytes were measured selectively. During G‐CSF administration neutrophil basal adhesion increased from 7.4 ± 3.9% (mean ± SD) to 55.8 ± 12.9% and 23.2 ± 4.4%, 4 and 7 d, respectively, after start of the administration. At the same time points eosinophil basal adhesion increased from 7.1 ± 2.4% to 37.7 ± 6.1% and 13.1 ± 5.3%, respectively. When adhesion was measured in the presence of Mn2+, which increases the functional activity of integrins, an even higher increase of neutrophil and eosinophil basal adhesion was noted 4 and 7 d, respectively, after start of G‐CSF administration. In parallel with the enhanced basal adhesion neutrophil adhesion to E‐selectin and ICAM‐1 and eosinophil adhesion to E‐selectin, VCAM‐1 and ICAM‐1 were significantly (P < 0.05) increased after 4 d of G‐CSF administration as was neutrophil cell surface expression of CD11b and CD18. In vitro G‐CSF induced minimal changes of granulocyte basal adhesion and inhibition of the adhesion to E‐selectin. 10 ng/ml TNFα significantly increased neutrophil and eosinophil basal adhesion and adhesion to VCAM‐1 and ICAM‐1. In summary, administration of G‐CSF to healthy subjects induced enhanced adhesion of neutrophil and eosinophil granulocytes, probably mediated by an increase of the functional capacity of β1‐ and β2‐integrins. The induction of increased levels of TNFα might be one mechanism behind the in vivo effect of G‐CSF administration.

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Recombinant granulocyte colony-stimulating factor administration to healthy volunteers: induction of immunophenotypically and functionally altered neutrophils via an effect on myeloid progenitor cells

Cited by 156 publications

References 44 publications

Ex vivo neutrophil function in response to three different doses of glycosylated rHuG‐CSF (Lenograstim)

Ex vivo neutrophil function in response to three different doses of glycosylated rHuG‐CSF (Lenograstim)

Leucocyte alkaline phosphatase identifies terminally differentiated normal neutrophils and its lack in chronic myelogenous leukaemia is not dependent on p210 tyrosine kinase activity

Effects of in vivo administration of G‐CSF on neutrophil and eosinophil adhesion

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